MXPA96003034A - Pharmaceutical product that comprises a salicilatode a beta sterify blocker - Google Patents

Abstract

Salicylates of esterifiable blockers are described, especially Atenolol-O-Aspirinate, Metoprolol-O-Aspirinate, Pindolol-O-Aspirinate, and processes for their preparation.

Description

PHARMACEUTICAL PRODUCT OUE UNDERSTANDS A BALICILATO OF A ESSENTIAL BETA BLOODER The invention relates to pharmaceutical products. The term "β-blocker" as used in this specification refers to pharmacologically active β-blocking compounds that are released or act as prophylactics against cardiovascular diseases, including hypertension, angina pectoris (pain in the heart muscle), heart failure , or after a heart attack (infarction after myocardial infarction). Beta-adrenoceptor blocking or antagonistic agents are competitive inhibitors of catecholase in the beta-adrenergic receptor sites. The main effect of β-blockers is to reduce cardiac activity by decreasing or preventing the stimulation of the beta-adrenergic receptor. Β-blockers inhibit renin secretion, and alter the sensitivity of the baroreceptor reflex, and also block the sympathetic impulse to the heart. This reduces chronotropic and inotropic responses during exercise and tension, thus limiting oxygen requirements. Β-blockers are effective in reducing the severity and frequency of angina per exercise (ie, pain in the heart caused by exercise), that is, angina pectoris. Β-blockers are also important in antihypertensive therapy (lowering blood pressure). It is thought that this is achieved through the reduction of cardiac production, and in the inhibition of renin secretion and a change in the sensitivity of baroreceptor reflux. Aspirin (acetylsalicylic acid) has been widely used for many years as an analgesic / antipyretic and anti-inflammatory agent. As such, it is a very useful drug. In more recent years, however, it has been discovered that aspirin has a powerful effect against platelets. Platelets are microscopic particles within the blood that, under certain circumstances, can adhere to each other to form a thrombus (clot). Aspirin prevents the adhesion of platelets to each other, and therefore helps prevent the occurrence of a heart attack or its complications. According to the invention, there is provided a pharmaceutical product comprising a salicylate of an esterifiable β-blocker. The term "salicylate" as used in this specification, refers to a salicylate or a salt, ester, derivative, complex thereof, or salts of the ester, derivative, or complex having an activity against platelets.

Preferably, the β-blocker can be directly esterified. In other words, the β-blocker has a hydroxy group that is available for esterification. In a particularly preferred embodiment of the invention, the product is formed by the esterification of an ß-esterifiable blocker with acetylsalicylic acid. Preferably the β-blocker is Atenolol. The invention further provides Atenolol-O-aspirinate and enantiomers thereof. In another case, the β-blocker is Metoprolol. The invention also provides Metoprolol-0-Aspirinate. In a further embodiment, the ß blocker is Pindalol. The invention also provides Pindalol-O-Aspirinate. The invention also provides a process for the preparation of a pharmaceutical product of the invention, by esterification of a β-blocker esterifiable with acetylsalicylic acid. In another embodiment, the process involves esterifying an ß esterifiable blocker with salicylic acid. In one of the embodiments of the invention, the process comprises the steps: protecting the secondary amine group in the β-blocker; activating the carboxyl group in salicylic acid or derivative thereof; direct coupling of the activated carboxyl group of salicylic acid or derivative thereof; and removing the protective groups of the secondary amine group in the β-blocker. In this case, the secondary amine group in the β-blocker is protected by forming an N-BOC derivative of the secondary amine of the β-blocker., and after coupling, the N-BOC protecting group is removed. In one embodiment of the invention, the N-BOC derivative of the β-blocker is formed by the reaction between the secondary amine of the β-blocker and tertiary dibutyl in t-BuOH / H20 to form the tertiary butyloxic carbamide derivative. Preferably, the protecting group of N-BOC is removed using trifluoroacetic acid to form the trifluoroacetate salt of Aspirinate. Typically, the process includes the step of forming the Aspirinate base of the β-blocker by extraction from a slightly alkaline medium. Preferably, the process includes the steps of acidifying an alcohol solution of the Aspirinate base in an acid to form a pharmaceutically acceptable salt. In another embodiment of the invention, the carboxyl group of salicylic acid or derivative thereof is activated by one or more of: acid chloride formation; pentafluorothioester formation; or on-site formation of 2,6-dichlorobenzoyl anhydride. In one case, the β-blocker is coupled with the acetylsalicylic acid derivative having an activated carboxyl group. In another case, the β-blocker is coupled with a salicylic acid derivative having a protected hydroxy group. Preferably, the hydroxy group is protected by the formation of benzyl ether. In a preferred embodiment, the salicylic acid is converted to 0-benzyloxybenzoic acid. The process also includes removing the hydroxy protecting group from salicylic acid after coupling. Typically, the hydroxy group of the protected salicylic acid is removed by hydrogenolysis. In a preferred embodiment of this aspect of the invention, after removal of the protecting group, the salicylic acid derivative is acylated. In one embodiment of the invention, the process comprises the steps of: forming a hydroxy group of protected salicylic acid; forming an N-BOC derivative of the secondary amine of the β-blocker; coupling the protected salicylic acid with the β-blocker of N-BOC; remove the protecting group from the hydroxy group of salicylic acid; acylate salicylic acid; and remove the N-BOC protecting group. In another embodiment, the process comprises the steps of: forming an N-BOC derivative of the secondary amine of the β-blocker; directly coupling the N-BOC derivative of the β-blocker with acetylsalicylic acid; Remove the N-BOC protecting group. In a further possible embodiment, the process comprises the steps of: forming a pentafluorothiophenolic ester of acetylsalicylic acid; forming an N-BOC derivative of the secondary amine of the β-blocker; directly coupling the pentafluorothiophenolic ester with the N-BOC derivative of the β-blocker; and remove the N-BOC protecting group.

In another embodiment, the process comprises the steps of: forming acetylsaliloyl chloride; forming an N-BOC derivative of the secondary amine of the β-blocker; directly coupling the β-blocker of N-BOC with acetylsaliloyl chloride; and remove the N-BOC protecting group. In these cases, the process of preference includes the step of, after removing the protective group, forming the base of β-blocker aspirinate; and optionally, forming pharmaceutically acceptable salts thereof by acidification of an alcoholic solution of the base using appropriate acids. The invention further provides a pharmaceutical product as long as it is prepared by a process of the invention. The invention also provides a pharmaceutical composition that includes a pharmaceutical product of the invention. The composition is preferably in the form of a tablet or capsule. The invention will be understood more clearly from the following description thereof, given by way of example only. The β-blockers and their salts, their enantiomers and their salts, their derivatives (eg, esters) and their salts, are all 2-ethanolic amine derivatives. More specifically, they are compounds of the formula: HO-CH-CH2-NH-R R1 wherein R = ip, tb, or other, and R1 represents different substituents. The following are some examples of them: Compound Form NR Acetabulol HCl P Alprenolol HCl iP Amosulalol HCl - Arotinolol HCl tb Atenolol iP Base Befunolol HCl iP Betaxolol HCl iP Bevantolol HCl - Bisopropolol He ifumarate ÍP Bopindolol Hemimaleate tb Bucindolol HCl - Bufetolol HCl tb Bufuralol HCl tb Bunitrolol HCl tb Bupranolol HCl tb Butofilolol Maleate tb Carazolol HCl p Carteolol HCl tb Carvedilol Base Celiprolol HCl tb Cetamolol HCl tb Cloranolol HCl tb Dexpropranolol HCl iP Diacetolol HCl Dilevalol HCl Epanolol Base Esmolol HCl 1P Indenolol HCl ip Labetalol HCl ip Levobunolol HCl ip Levomoprolol HCl iP Medroxalol HCl Mepindolol Sulfate iP Metipranolol IP Base Metoprolol iParture iPoprolol HCl iP Nadolol Base tb Nifenalol HCl iP Nipradilol iP Base Oxprenolol HCl iP Penbutolol Sulfate tb Pindolol Base ip Practolol HCl ip Pronetalol HCl ip Propanolol HCl ip Sotalol HCl ip Sulfinalol HCl - Talinolol Base ip Tertatolol HCl tb Timolol HemiMaleate tb Toliprolol HCl ip ip = iso-Propyl tb = tertiary butyl other = several EXAMPLE 1 Synthesis of Atenolol-o-aspirinate "Atenolol" is acetamide (RS) -4- (2-hydroxy-3-isopropylaminopropoxy) phenyl - British Pharmacopoeia 1993, Volume I, page 55. Materials: Acetylsalicylic acid Sigma Ltd MW 180.16 Atenolol MW 266.34 Dicyclohexyl Carbodiimide (DCC) Sigma Ltd MW 206-33 Dimethyl Aminopyridine (DMAP) Sigma Ltd MW 122.20 Method To a stirred solution of acetylsalicylic acid (3.6 grams, 0.02 moles) in 30 milliliters of dry dichloromethane, dimethyl aminopyridine (0.5 grams) was added and Atenolol (5.32 grams, 0.02 moles). Dicyclohexyl carbodiimide (4.2 grams) was gradually added at 0 ° C, and the reaction mixture was stirred for 15 minutes. The icy bath was removed, and the mixture was stirred for another 3 hours. The precipitated urea was removed by filtration, and the filtrate was evaporated in vacuo. The filtrate was recovered dichloromethane, and then washed with portions of 2 x 25 milliliters of 20 percent citric acid, and then with 2 x 25 milliliter portions of a saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed in vacuo to yield the semisolid product of Atenolol-O-aspirinate (30 percent yield). The product was characterized as Atenolol-O-aspirinate used FTIR and NMR as shown in Figures 1 and 2. FTIR (thin film) vCO: 1747, 1650 cm-1 NMR (CDC13) 300 MHz: 1.25, double CH (CH3) ) 2: 2.6-2.96 CH2 and CH: 3. 485 ARCH2CO singlet: 2.45 ArOCOCH3 singlet: 6.9-8.25 aromatics. (8H).

This method is illustrated schematically in Appendix 1, and is an adaptation of the method described by Neises and Steglich, Agnew Chem. Int. Ed. 17 (1978) No. 7, page 522-524. Other suitable direct esterification methods are given in Larock, R.C., "Comprehensive Organic Transformations" pages 966-972, inclusive, published by VCH 1989. The product has the following structure: Atenolol-O-aspirinate and enantiomer EXAMPLE 2 The product of Example 1 can also be prepared by indirect esterification. 2A Esterification by acetylsalicyloyl chloride (Appendix 2A) Materials: Acetylsalicylic acid Sigma Thionyl chloride Aldrich Chemicals Atenolol Method 36 grams are placed in a 50-milliliter round bottom flask equipped with a reflux condenser with connected drying tube. of acetylsalicylic acid. 35.2 grams of thionyl chloride are added gradually over 5 minutes. The mixture is heated under a slight reflux for 75 minutes, and then cooled. Then the flask is transferred to a rotary evaporator in a fume hood, and the excess thionyl chloride is removed in vacuo. The required acetylsaliloyl chloride is identified by infrared (vCO 1784 c "1) and NMR (acetylmethyl 3H: 2.45 and aromatics 4H: 8.18 to 7.25). Atenolol (0.5 grams, 3.75 millimoles) is dissolved in 25 milliliters of chloroform in a flask of round bottom adapted with a drying tube, acetylsalicyloyl chloride (5.5 milliliters, 37.5 millimoles) is gradually added, and the solution is refluxed for 2 hours.The chloroform is evaporated in vacuo, and then the residue is recovered in ether. The ether is decolorized using charcoal, filtered, and the solvent is removed under vacuum, then the residue is dissolved in ethanol, and the product is recovered by precipitate using normal hexane as an oily semi-solid.The product (25 percent yield ) is characterized as Atenolol-O-aspirinate using FTIR and NMR according to the attached spectra.

This method is an adaptation of the method described by Anspach, R. et al., Ann. Chem, 367 172-180, 1909. The methods described by 1) Satchell Q, Rev, Chem. Soc, 17. 160-203 and 182-184, 1963, and 2) Scheithauer; Mayer Top. Sulfur Chem. 4, 1-373, 1979. Esterification of thiols to form esters can also be achieved by the treatment of carboxylic acids such as acetylsalicylic acids, with agents such as: Trisalkyl thioborates: Pelter et al., J. Chem. Soc. ., Perkin Trans. 1. 1672, 1977 Phenyldichlorophosphate or the appropriate polyphosphate ester. Immamoto et al., Synthesis 134, 1982. Liu and Sabesan, Can J. Chem 58, [2645, 1980]. Dellaria et al., Synth, Commun. 1J5, 1043, 1986. Chloroformate of alkyl and triethyl amine: Kim and Kim, J. Org. Chem. 50, 560, 1985. General: Arrieta et al., Synth. Commun. 13., 471, 1983 Haslam Tetrahedron 16, 2409-2433, 1980.

EXAMPLE 3: Atenolol Aspirinate Synthesis strategy used in the coupling of Atenolol with aspirin. In the following scheme 1 an alternative route for direct coupling of Atenolol with acetylsalicylic acid is described. The salicylic acid 1 was dialkyl by the formation of the benzyl ester, as well as the benzyl ether, and then the functional group of ester 2 was hydrolyzed back to the acid under basic conditions. The benzyl ester formation of 1 was rapid (room temperature, 20 minutes). More vigorous conditions were required to form the benzyl ester (60 ° C, 2 hours, 55 percent). The hydrolysis of the benzyl ester of 2 was then carried out under standard basic conditions, which gave the acid 3 in a yield of 95 percent. One of the most successful methods for the coupling of alcohol units with organic acids is by means of the lactonization method, described by Yamaguchi et al .: Yamaguchi et al., Bull. Chem. Soc. Japan, 1979, 52., 1989, Waanders et al., Tetrahedron Letters, 1987, 2, 2409. The highest yield of ester 5 was obtained using the following method. The 3-aminopyridine dimethyl acid (4 equivalents) in toluene was dried by azeotropic distillation, and a solution of 2,6-dichlorobenzoyl chloride (1 equivalent) in dry toluene was added to the dry solution. After refluxing this solution for 5 minutes, 1 equivalent of N-BOC-Atenolol 4 was added. After refluxing for 25 minutes, analysis of the solution by TLC implied that all of the acid was consumed. After work (see experimental section), ester 5 was isolated in 95 percent after chromatography. Hydrogenolysis of benzyl ether 5 was performed using 1 equivalent by weight of 10 percent palladium 0 on carbon to benzyl ether 5 in ethanol / ethyl acetate. After work, phenol was isolated in a quantitative yield. Acetylation of the phenol proceeded neatly, yielding acetate 6 in a 90 percent yield after work. 5 Preparation of the ester 5"*" To a solution of salicylic acid 1 (75 milligrams, 0.54 millimoles) in MeOH-H20 (30 milliliters, 10: 1), aqueous Cs2CO3 was added until the pH of the solution was 0 slightly. alkaline (pH 7.5-8.0). The solvent was then evaporated on a rotary evaporator to leave an oil, to which toluene (30 milliliters) was added. Evaporation of the solvent on the rotary evaporator left a white solid of the cesium salt, which was dissolved in dimethyl formamide (15 milliliters). To this solution was added benzyl chloride (0.14 grams, 1.1 millimoles, 2.0 equivalents). The mixture was allowed to stir at room temperature for 20 minutes, at which time the TLC showed that the formation of the benzyl ester had taken place. The solution was then heated to 60 ° C, and after 2 hours, the TLC showed that the formation of benzyl ether 2 had taken place. After cooling to room temperature, the mixture was divided between ether-water (1: 1). , 120 milliliters). The organic layer was isolated, and the aqueous layer was extracted with ether (2 x 50 milliliters). The combined organic layers were washed with water and dried with MgSO4. Filtration followed by evaporation of the solvent left an oil, which was passed through a plug of silica, eluting with hexane-ethyl acetate (30: 1), which gave the benzyl ether 2 (95 milligrams, 55%). cent) as an oil. Benzyl ether 2 (95 milligrams, 0.3 mmol) was then dissolved in a solution of 2M NaOH in tetrahydrofuran-Me-OH-H20 (3: 3: 2) (16 milliliters), which was then refluxed. After 2 hours, the TLC showed that the hydrolysis of the benzylester 2 was finished. The removal of the volatiles on the rotary evaporator left an oil, which was divided between ether (50 milliliters) and water (50 milliliters). The aqueous phase was extracted and thereto was added dilute aqueous HCl (1M, 100 milliliters) and ether (100 milliliters). The organic layer was isolated, and the aqueous layer was extracted with ether (2 x 50 milliliters). The combined organic extracts were washed with water, dried with MgSO 4, and filtered. The evaporation left an acid 3 as a gum, which was dissolved in toluene (50 milliliters), and dimethyl aminopyridine (146 milligrams, 1.2 mmol) was added to this solution. This solution was then completely dried by azeotropic distillation, and a solution of 2,6-dichlorobenzoyl chloride (62.5 milligrams, 0.3 mmol) in dry toluene (5 milliliters) was added to the dry solution. Then the solution was refluxed for 5 minutes, and then N-BOC-Atenolol (109 milligrams, 0.3 mmol, 1 equivalent) was added. After 10 minutes of reflux, the TLC showed that the formation of ester 5 was completed. Evaporation of the solvent on a rotary evaporator left a gum, which was dissolved in DCM and passed through a plug of silica, eluting with ethyl acetate to give the ester 5 as an oil (160 milligrams, 93 percent); 5H (selected peaks only) 1.11 (6H,, CH (CH3) 2), 1.45 (9H, S, (CH3) 3C-0), 3.46 (2H,?, PhCH_2CONH2), 3.56 and 4.13 (5H, m, OCH2CH -CH2NCH), 5.13 (2H, s, benzyl CH20), 5.53, 5.60 and 5.99 (3H, br, m, CH-OCO and C0NH2), 6.82-7.9 (13H,, aromatic proton resonances). dC (selected peaks only) 20.7 (2 x C, CH (CH3) 2, 28.4 (3 x C, CH3) 3C-0), 42.2 (IC, PhCH2CONH2), 67.7 and 71.9 (2C, -NCH2CHCH2OAr), 79.8 ( ÍC, (CH3) 3C-0), 113.5-158.1 (aromatic carbon resonances), 165.5 and 174.1 (2 XC, COOH and CONH2).

Hydrogenolysis of benzyl ether of 5 and Acetylation of the resulting phenol to give acetate 6. To a solution of 5 (0.1 grams, 0.17 mmol) in ethyl acetate (5 milliliters) and ethanol (5 milliliters), palladium was added to the 10 percent on charcoal (0.1 grams). The 0 hydrogenolysis of the benzyl ether was carried out at a pressure of 1 atmosphere under an atmosphere of hydrogen at room temperature. After 24 hours, the TLC indicated that a complete removal of the benzyl ester had taken place. The solvent was then removed on the rotary evaporator to leave a black gum. This was then dissolved in DCM, filtered, and the filtrate was concentrated and passed through a stopper. - - * - silica gel eluting with ethyl acetate. Evaporation of the eluent left the phenol as an oil (79 milligrams, 95 percent). dH (selected peak only) 10.69 (1H, s, OH 0 phenolic). Then the phenol was dissolved in anhydrous DCM (5 milliliters), and Et3N (65 milligrams, 0.65 millimoles) and dimethyl aminopyridine (79 milligrams, 0.65 millimoles) were added. After stirring for 4 hours at room temperature, analysis by TLC showed that all the phenol had been consumed. Evaporation of the solvent left an oil, which was passed through a plug of silica, eluting with ethyl acetate. Evaporation of the eluent gave acetate 6 as a colorless oil (81 milligrams, 94 percent), dH (selected peak only) 2.32 (3H, s, CH3C? O).

Removal of the N-BOC protecting group from 6 to give the aminotrifluoroacetate salt. To a stirred solution of TFA (3 milliliters) in anhydrous DCM (3 milliliters) at room temperature, N-BOC carbamate 6 (81) was added. milligrams, 0.15 millimoles). After 3 hours of stirring at 0 ° C, the volatiles were removed by evaporation under reduced pressure. DCM (3 x 20 milliliters) was added to the residue, and it was removed by evaporation under reduced pressure to leave the alkyl ammonium trifluoroacetate salt 7 as a clear colorless oil. dH (selected peaks only) 1.33 (6H, m, CH (CH3) 2), 2.29 (3H, s, CH3COO), 3.44 (2H, s, PhCH2CONH2), 3.49 and 4.23 (5H,, OCH2CH2NCH), 5.53, 5.60 and 6.66 (3H, br, m, CH-OCO and C0NH2), 6.85 and 7.08 (4H, 2d, proton resonances of benzene acetamide), 7.09, 7.28, 7.57 and 7.99 (4H, d, t, t, d, resonances aromatic protons of Aspirin). dC (selected peaks only) 19.0 (2 x C, CH (CH3) 2, 21.4 (1 x C, CH3CO-0), 42.2 (IC, PhCH2CONH2), 55.0 and 70.1 (2 x C, CHCH2NCH (CH3) 2, 67.7 and 71.9 (2C, -NCH2-CHCH2OAr), 115 and 132 (2 x C, CH resonances of acetamide benzene), 124, 128, 134 and 136 (4 x C, aromatic CH resinances of Aspirin), 122, 130, 152 and 157 (4 x C, Quaternary aromatic carbons), 157, 164 and 172 (3 x C, COO, COO, and CONH2).

Legend for the spectroscopic data of Figures 3 to 14 inclusive. Fig. 3: 1H NMR Compound 5 Scheme 1 previous Fig. 4: D DEEPPTT RRMMNN C Coommppuueessttoo 55 Scheme 1 previous Fig. 5: 1 133CC RRMMNN C Coommppuueessttoo 55 Scheme 1 previous Fig. 6: 1 LHH RRMMNN C Coommppuueessttoo 55a (phenol) Scheme 1 previous Fig. 7: 1 133CC RRMMNN CCoommppuueessttoo 55a (phenol) Scheme 1 previous Fig. 8: DDEEPPTT RRMMNN CCoommppuueessttoo 55a (phenol) Scheme 1 previous Fig. 9: 1H NMR Compound 6 Scheme 1 previous Fig. 10: DEPT NMR Compound 6 Scheme 1 previous Fig. 11: 13 C NMR Compound 6 Scheme 1 above Fig. 12: LH NMR Atenolol aspirinate, salt form Scheme 1 above Compound 7 Fig. 13: DEPT NMR Atenolol aspirinate, salt form Scheme 1 above Compound 7 Fig 14 : 13C NMR Atenolol Aspirinate, salt form Scheme 1 above Compound 7 Preparation of Atenolol Aspirinate and conversion into its hydrochloride, fumarate, and tartrate salts. Atenolol Aspirinate trifluoroacetate (0.2 grams) was dissolved in 5 milliliters of methanol, and treated with 10 percent aqueous NaHCO3 (100 milliliters). The aqueous solution was extracted with 3 x 30 milliliters of dichloromethane. The organic solution was dried (Na2SO4) and evaporated, yielding Atenolol aspirinate. The Atenolol aspirinate was dissolved in 5 percent methanolic HCl, and stirred for 30 minutes. The solvent was evaporated to give the hydrochloric salt. The treatment of Atenolol aspirinate with 0.5 equivalents of fumaric or tartaric acid in methanol produced the corresponding fumarate and tartrate salts upon evaporation of the solvent.

Scheme 1 H.N EXAMPLE 4 - Metoprolol Aspirinate The title compound was prepared according to the reaction scheme set forth below.

Synthesis of O-benzyloxybenzoic acid 4 Benzylation of salicylic acid: "Salicylic acid (1) was dissolved in methanol / water (10: 1), treated with 1 molar equivalent of K2CO3, and stirred at room temperature for 1 hour. The di-ionic salt 2 obtained by evaporating the solvent was treated with 2 molar equivalents of benzyl bromide in dimethyl formamide, and heated at 60 ° C for 4 hours. After work and silica gel chromatography. The desired product, dibenzyl 3 salicylate, was obtained in a 61 percent yield, in addition to benzyl salicylate (30 percent).

Hydrolysis of dibenzyl salicylate Dibenzyl 3 salicylate (0.3 grams) was dissolved in 10 milliliters of a tetrahydrofuran / methanol / water solution (2: 2: 2), and an equal volume of 2M NaOH was added. The solution was refluxed for 15 minutes until the starting material disappeared as evidenced by TLC. The solution was poured into 100 milliliters of water, and extracted with 3 x 30 milliliters of ether. The aqueous fraction was acidified to a pH of 3-4 with 2M HCl. The acid solution was extracted with 3 x 30 milliliters of ether, and the combined organic fractions were dried (Na 2 SO 4) and evaporated, to give the title compound, O-benzyloxybenzoic acid 4 as a solid.

Synthesis of N-BOC-Metoprolol 5 Methoprolol (1.0) was dissolved in 5 milliliters of t-BuOH / H20 (10: 1) and tertiary dibutyl dicarbonate (0.82 grams) was added in 5 milliliters of t-BuOH / H20 (10: 1). The solution was stirred for 20 hours, and then poured into 100 milliliters of water. The solution was extracted with 3 x 30 milliliters of petroleum ether (boiling point: 40-60 ° C). The combined organic fractions were dried (Na2SO4) and concentrated. Column chromatography by evaporation using 3: 1 petroleum ether: ether gave the title compound as a viscous liquid.

Synthesis of O-Benzyloxybenzoate of N-BOC-Metoprolol 6 O-benzyloxybenzoic acid 4 (0.11 grams) and 4-dimethyl aminopyridine (0.24 grams) 2343 were dissolved in 20 milliliters of dry toluene. The solution was heated to reflux, and 2,6-dichlorobenzoyl chloride (0.10 grams) was added. After 10 minutes, under reflux, N-BOC-Metoprolol (0.18 grams) was added in 5 milliliters of dry toluene, and the reflux was continued for another 30 minutes. The mixture was filtered through silica, and the filtrate was evaporated, yielding the title compound in a quantitative yield.

Debenzylation of O-benzyloxy from N-BOC-Metoprolol 6 The above compound was dissolved in 20 milliliters of ethanol / dichloromethane (1: 1), and 1 equivalent of palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through silica, and the filtrate was evaporated to give N-BOC-Metoprolol salicylate (7) in a quantitative yield as a viscous liquid.

Acetylation of N-BOC-Metoprolol salicylate: The above compound was dissolved in 20 milliliters of dry dichloromethane. 3 molar equivalents of acetic anhydride were added with stirring. Then 2 molar equivalents of dry triethyl amine and 4 molar equivalents of dimethyl aminopyridine were added, and the solution was stirred for 2 hours at room temperature. The solvent was evaporated, and the residue was subjected to slow column chromatography using petroleum ether: ether (1: 1) as eluent. Aspirinate of N-BOC Metoprolol (8) was obtained as a viscous liquid. (Yield: 80 percent).

The presence of both the aspirin fraction and that of Metoprolol in the product was confirmed by y In the XH NMR, the methyl acetate group appeared as a 3H singlet at 2.32 ppm. The aryl hydrogens of the aspirin fraction gave rise to 4 multiplets between 6.8 and 8.1 ppm. The last multiplet was assigned to the aryl hydrogen beta of the ester carbonyl group. The remaining signs, with the exception of the singlet 9H at 1.47 ppm due to the tertiary butyl group, are similar to those exhibited by Metoprolol. The exception is ester hydrogen that moves downfield to 5.6 ppm, and appears as a broad multiplet. This, by itself, is strong evidence that the desired coupling has taken place. The corresponding hydrogen of Metoprolol is seen in 4 ppm. The aromatic protons of the metoprolol fraction give rise to two multiplets at 7.28 ppm and 7.54 ppm. The methane proton of the isopropyl amine group and the methylene of ArOCH2-, are present as a broad multiplet between 3.8 and 4.3 ppm. The methylene protons of -CH2OCH3 and the amino methylene protons give a multiplet at 3.4-3.65 ppm. The methoxy group gives a singlet at 3.34 ppm. The triplet at * 2.81 ppm is assigned to the methylene protons of ArCH2-. The acetate protons produce a singlet at 2.32 ppm. The tertiary butyl group is shown as a singlet at 1.47 ppm. The doublet remaining at 1.14 ppm is due to the methyl protons of the isopropyl amine. 13 C NMR (ppm) 20.94, 28.37, 29.6, 35.2, 58.54, 67.63, 72.12, 73.73, 79.87, 114.48, 123.1, 123.69, 125.86, 129.72, 131.47, 131.74, 133.8, 150.66, 156.95, 163.77, 169.48.

Metoprolol Aspirinate Trifluoroacetate 9: N-BOC-Metoprolol Aspirinate 8 (0.05 grams) was dissolved in 10 milliliters of dry dichloromethane, and trifluoroacetic acid (3 milliliters) was added. The solution was stirred for 1 hour. The solvent was evaporated, producing the compound as a viscous liquid. 1H NMR: The main difference between the spectrum and that of its precursor is the absence of the 9H singlet at "1.4 ppm, indicating that the tertiary-carbonyl butoxy group has been successfully removed, with a broad peak at" 8.1 ppm, which it is due to protons on quaternary nitrogen. Otherwise, there is little difference in the spectra as easily confirmed by a visual inspection. Methyl isopropyl amine groups appear as a double at 1.36 ppm. The methyl acetate group appears as a singlet at 2.31 ppm. The methylene group of ArCH2- is seen as a triplet at 2.83 ppm. The methoxy group appears at 3.36 ppm as a singlet. The methane proton of the isopropyl amine group and the methylene of -CH2OCH3 give rise to overlapping multiplets at 3.42 to 3.7 ppm. The doublet at 4.24 ppm is assigned to the methylene hydrogens of ArOCH2-. The broad multiplet at 5.6 ppm is assigned to the methane proton of the ester. The aromatic protons of Metoprolol are present as two multiplets at 6.83 ppm and 7.12 ppm. The multiplet at 7.12 ppm also contains signals for one of the protons of aspirinate. The three remaining multiplets at 7.3 ppm, 7.59 ppm, and 7.95 ppm, are due to the protons of aspirinate. 13C NMR (ppm) 18.55, 18.81, 20.9, 29.6, 34.93, 45.74, 51.77, 58.4, 67.11, 69.24, 73.61, 114.44, 121.9, 123.48, 126.22, 129.94, 131.62, 132.13, 134.74, 150.35, 156.16, 159.86, 160.37 , 160.89, 161.4, 164.16, 170.53. Legend for the spectroscopic data of Figures 15 to 23 inclusive. Fig. 15: H NMR Compound 5 Scheme 2 Fig. 16: DEPT NMR Compound 5 Scheme 2 Fig. 17A: 13C NMR Compound 5 Scheme 2 Fig. 17B: DEPT NMR Compound 5 (comparison) Scheme 2 Fig. 18: LH NMR Compound 8 Scheme 2 Fig. 19: 13 C NMR Compound 8 Scheme 2 Fig. 20: DEPT NMR Compound 8 Scheme 2 Fig. 21: 1H NMR Compound 9 Scheme 2 Fig. 22: 13C NMR Compound 9 Scheme 2 Fig. 23: DEPT NMR Compound 9 Scheme 2 Preparation of Aspirinate of Metoprolol and conversion into its salts of hydrochloride, fumarate, and tartrate. Metoprolol Aspirinate trifluoroacetate (0.2 grams) was dissolved in 5 milliliters of methanol, and treated with 10 percent aqueous NaHCO3 (100 milliliters). The aqueous solution was extracted with 3 x 30 milliliters of dichloromethane. The organic solution was dried (Na2SO4) and evaporated, yielding Metoprolol aspirinate. The aspirinate of Metoprolol was dissolved in 5 percent methanolic HCl, and stirred for 30 minutes. The solvent was evaporated to give the hydrochloric salt. The treatment of aspirinate of Metoprolol with 0.5 equivalents of fumaric or tartaric acid in methanol produced the corresponding fumarate and tartrate salts upon evaporation of the solvent.

ESOUEMA 2 (i) (2) 1. 4-dimethyl aminopyridine (4 equivalents) / toluene /? 2. 2,6-Dichlorobenzolyl Chloride (1 equivalent) /? Alternative Synthesis of Metoprolol Aspirinate To a stirred solution of acetylsalicylic acid (2) (0.05 grams, 0.27 millimoles) in 20 milliliters of dry dichloromethane, dimethyl aminopyridine (0.005 grams) and N-BOC-Metoprolol (1) (0.1 grams, 0.27 millimoles) were added. The solution was cooled to 0 ° C, and dicyclohexyl carbodiimide (0.06 grams, 0.27 mmol) was added. The reaction was stirred at 0 ° C for 5 minutes, and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was washed with 3 x 30 milliliters of 1M HCl. the organic layer was washed with 3 x 30 milliliters of water, and the combined organic layers were dried (Na S04) and evaporated. The residue was purified by slow column chromatography to give N-BOC-Metoprolol aspirinate (3) as a viscous liquid. This product was converted into Metoprolol Aspirinate Trifluoroacetate (4) in the manner already described.

CF3COOH. CHjOj SCHEME 3 Alternative Synthesis of Metoprolol Aspirinate Metoprolol aspirinate Scheme for the synthesis of aspirinate of metoprolol-Scheme 4 c% > H.H) «71 (ß) Synthesis of N-BOC-Pindolol (2): Pindolol (1) (0.93 grams, 3.74 millimoles) was dissolved in 5 milliliters of t-BuOH / H20 (10: 1), and tertiary dibutyl dicarbonate (0.82 grams, 3.74 millimoles) in 5 milliliters of t-BuOH / was added. H20 (10: 1). The solution was stirred for 20 hours, and then poured into 100 milliliters of water. The solution was extracted with 3 x 30 milliliters' of petroleum ether (boiling point: 40-60 ° C). The combined organic fractions were dried (Na2SO4) and concentrated. Column chromatography by evaporation using 3: 1 petroleum ether: ether gave the title compound as a viscous liquid. The synthesis of O-benzyloxybenzoic acid (3) has already been described (see the report on the synthesis of metoprolol aspirinate trifluoroacetate).

Synthesis of O-benzyloxybenzoate of N-BOC-Pindolol (4): O-benzyloxybenzoic acid (3) (0.11 grams) and 4-dimethyl aminopyridine (0.24 grams) were dissolved in 20 milliliters of dry toluene. The solution was heated to reflux, and 2,6-dichlorobenzoyl chloride (0.10 grams) was added. After 10 minutes under reflux, N-BOC-Pindolol was added (0.18 grams, 0.48 millimoles) in 5 milliliters of dry toluene, and the reflux was continued for another 30 minutes. The mixture was filtered through silica, and the filtrate was evaporated, yielding the title compound in a quantitative yield.

Debenzylation of O-benzyloxybenzoate from N-BOC-Pindolol (4): The above compound was dissolved in 20 milliliters of ethanol / dichloromethane (1: 1) and 1 equivalent of palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere for 5 hours. The suspension was filtered through silica, and the filtrate was evaporated to give N-BOC-Pindolol Salicylate (5) in a quantitative yield as a viscous liquid.

Acetylation of N-BOC-Pindolol Salicylate (5): The above compound was dissolved in 20 milliliters of dry dichloromethane. 3 molar equivalents of acetic anhydride were added with stirring. Then 2 molar equivalents of dry triethyl amine and 4 molar equivalents of dimethyl aminopyridine were added, and the solution was stirred for 2 hours at room temperature. The solvent was evaporated, and the residue was subjected to slow column chromatography using petroleum ether: ether (1: 1) as eluent. N-BOC-Pindolol Aspirinate (6) was obtained as a viscous liquid. (Yield of 86 percent).

Pindolol Aspirinate Trifluoroacetate (7): N-BOC-Pindolol Aspirinate (6) was dissolved in 10 milliliters of dry dichloromethane, and trifluoroacetic acid (3 milliliters) was added. The solution was stirred for 1 hour. The solvent was evaporated, yielding the title compound as a viscous liquid.

Pindolol Aspirinate (8) Pindolol Aspirinate Trifluoroacetate (0.1 grams) was dissolved in 5 milliliters of methanol, and treated with 10 percent aqueous NaHCO3 (100 milliliters). The aqueous solution was extracted with 3 x 30 milliliters of dichloromethane. The organic solution was dried (Na2SO4) and evaporated, yielding Pindolol aspirinate.

Conversion of Pindolol Aspirinate into its hydrochloride, fumarate salts. and tartrate: The Pindolol aspirinate was dissolved in 5 percent methanolic HCl, and stirred for 30 minutes. The solvent was evaporated to give the hydrochloride salt. The treatment of Pindolol aspirinate with 0.5 equivalents of fumaric or tartaric acid in methanol produced the corresponding fumarate and tartrate salts upon evaporation of the solvent. The products of the invention are useful, since there is provided, in a single chemical entity, a product that acts both as a β-blocker and also has activity against plate as described above. The products can be formulated in any suitable pharmaceutical composition using excipients or conventional vehicles. Typically, the pharmaceutical composition will be provided in a form for oral administration, preferably in a capsule or tabform.

It will be appreciated that the composition may include a diuretic and potassium salts in a single tablet or capsule. The diuretic may be frusemide, amiloride, hydrochlorothiazide, or a potassium dispersion diuretic such as spironolactone or trimterene. It will also be appreciated that some of the β-blocker aspirin, especially thiolol aspirinate, can be formulated as eye drops, ie, for local application, in the treatment of ocular hypertension and glaucoma. It will be appreciated that, although the invention has been specifically described with reference to aspirinates of some β-blockers, it can also be applied to aspirinates of other ß-esterifiable blockers. The invention is not limited to the embodiments described hereinabove, which may be varied in detail.

APPENDIX 1 Synthesis of Atenolol-O-Aspirinate CH2CONH2 DMAP DCC APPENDIX 2 Esterification by means of acetylsalicyloyl chloride Atenolol-O-aspirinate

Claims (38)

1. CLAIMS 1. A pharmaceutical product comprising a salicylate of an esterifiable β-blocker.
2. 2. A pharmaceutical product as claimed in claim 1, wherein the β-blocker is indirectly esterifiable.
3. 3. A pharmaceutical product as claimed in claim 1, wherein the β-blocker is directly esterifiable.
4. 4. A pharmaceutical product as claimed in claim 3, wherein the β-blocker is atenolol.
5. 5. Atenolol-O-aspirinate.
6. 6. A pharmaceutical product as claimed in claim 3, wherein the β-blocker is Metoprolol.
7. 7. Metoprolol-O-Aspirinate.
8. 8. A pharmaceutical product as claimed in claim 3, wherein the β-blocker is Pindalol.
9. 9. Pindalol-O-Aspirinate.
10. 10. A pharmaceutical product substantially as described hereinabove with reference to the examples.
11. 11. A process for the preparation of a pharmaceutical product as claimed in any of the preceding claims, which comprises esterifying an ß-esterifiable blocker with acetylsalicylic acid.
12. 12. A process for the preparation of a pharmaceutical product as claimed in any of claims 1 to 10, which comprises esterifying a β esterifiable block with salicylic acid.
13. 13. A process for the preparation of a pharmaceutical product as claimed in any of claims 1 to 11, which comprises the steps of: protecting the secondary amine group in the blocker fl; activating the carboxyl group in salicylic acid or derivative thereof; directly coupling the activated carboxyl group of the salicylic acid or derivative thereof, with the protected β-blocker; and removing the protective groups of the secondary amine group in the β-blocker. A process as claimed in claim 13, wherein the secondary amine group in the β-blocker is protected by forming an N-BOC derivative of the secondary amine of the β-blocker, and after coupling, the protective group of the β-blocker is removed. N-BOC 15. A process as claimed in claim 14, wherein the N-BOC derivative of the β-blocker is formed by the reaction between the secondary amine of the β-blocker and tertiary dibutyl in t-BuOH / H20 to form the carbamide derivative tertiary butyroxy 16. A process as claimed in claim 14 or 15, wherein the protecting group of N-BOC is removed using trifluoroacetic acid to form the trifluoroacetate salt of Aspirinate. 17. A process as claimed in the claim 16, wherein the process includes the step of forming the β-blocker aspirinate base by extraction from a slightly alkaline medium. 18. A process as claimed in the claim 17, wherein the process includes the steps of acidifying an alcoholic solution of the aspirinate base in an acid to form a pharmaceutically acceptable salt. 19. A process as claimed in any of claims 13 to 18, wherein the carboxyl group of the salicylic acid or derivative thereof is activated by one or more of: acid chloride formation; pentafluorothioester formation; or on-site formation of 2,6-dichlorobenzoyl anhydride. 20. A process as claimed in any of claims 13 to 19, wherein the β-blocker is coupled to the acetylsalicylic acid derivative having an activated carboxyl group. 21. A process as claimed in any of claims 13 to 19, wherein the β-blocker is coupled with a salicylic acid derivative having a protected hydroxy group. 22. A process as claimed in claim 21, wherein the hydroxy group is protected by benzyl ether formation. 23. A process as claimed in the claim 21 or 22, wherein the salicylic acid is converted to 0-benzyloxybenzoic acid. 24. A process as claimed in any of claims 21 to 23, which includes the step of removing the hydroxy protecting group from salicylic acid after coupling. 25. A process as claimed in claim 24, wherein the hydroxy group of the protected salicylic acid is removed by hydrogenolysis. 26. A process as claimed in the claim 24 or 25, wherein, after removal of the protecting group, the salicylic acid derivative is acylated. 27. A process for the preparation of a pharmaceutical product as claimed in any of claims 1 to 10, which comprises the steps of: forming a hydroxy group of protected salicylic acid; forming an N-BOC derivative of the secondary amine of the β-blocker; coupling the protected salicylic acid with the β-blocker of N-BOC; remove the protecting group from the hydroxy group of salicylic acid; acylate salicylic acid; and remove the N-BOC protecting group. 28. A process for the preparation of a pharmaceutical product as claimed in any of claims 1 to 10, which comprises the steps of: forming an N-BOC derivative of the secondary amine of the β-blocker; directly coupling the N-BOC derivative of the β-blocker with acetylsalicylic acid; Remove the N-BOC protecting group. 29. A process for the preparation of a pharmaceutical product as claimed in any of claims 1 to 10, which comprises the steps of: forming a pentafluorothiophenolic ester of acetylsalicylic acid; forming an N-BOC derivative of the secondary amine of the β-blocker; directly coupling the pentafluorothiophenolic ester with the N-BOC derivative of the β-blocker; and remove the N-BOC protecting group. 30. A process for the preparation of a pharmaceutical product as claimed in any of claims 1 to 10, which comprises the steps of: forming acetylsaliloyl chloride; forming an N-BOC derivative of the secondary amine of the β-blocker; directly coupling the β-blocker of N-BOC with acetylsaliloyl chloride; and remove the N-BOC protecting group. 31. A process as claimed in any of claims 27 to 30, which includes the step of, after removing the protecting group, forming the β-blocker aspirinate base; and optionally, forming pharmaceutically acceptable salts thereof by acidification of an alcoholic solution of the base using appropriate acids. 32. A process substantially as described hereinabove with reference to the examples. 33. A pharmaceutical product as long as it is prepared by a process as claimed in any of claims 11 to 31. 34. A pharmaceutical composition that includes a pharmaceutical product as claimed in any of claims 1 to 10 or 32. 35. A pharmaceutical composition as claimed in claim 34, in the form of a tablet or capsule. 36. A pharmaceutical composition as claimed in claim 34 or 35, wherein the composition includes a diuretic and potassium salts. 37. Timolol aspirinate for local application in the treatment of ocular hypertension and glaucoma. 38. A pharmaceutical composition substantially as described hereinabove with reference to the examples.